Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthesis of α‑Ketone-isoquinoline Derivatives via Tandem Ruthenium(II)-Catalyzed C−H Activation and Annulation Xiao-Lin Wu and Lin Dong* Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
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S Supporting Information *
ABSTRACT: A new ruthenium(II)-catalyzed tandem C−H activation/ cyclization/hydrolysis cascade process of 2H-imidazoles and alkynes for facile and regioselective access to α-ketone-isoquinolines has been successfully developed. 2H-Imidazole as the novel traceless directing group has been well applied in this paper. The protocol features mild reaction conditions and easily accessible starting materials, and α-ketone-isoquinolines could be applied to further construct more complex heterocyclic compounds.
I
α-substituted isoquinolines were only limited to amine, ester, ether, α-alkyl, and aryl groups.8 In addition, 2H-imidazole as the directing group has not been studied in C−H activation yet.9 Therefore, there is increased interest in developing α-ketone isoquinoline derivatives.10 Herein, we report a less expensive ruthenium(II)-catalyzed cascade reaction to build novel α-ketone-isoquinoline derivatives via C−H activation/ cyclization/hydrolysis of imide into the carbonyl group cascade process of 2H-imidazoles and alkynes (Scheme 1, eq 2). It is worth mentioning that the 2H-imidazoles in this cascade reaction can act as a traceless directing group. We commenced our investigations by examining the cascade cyclization between 2,2,4-trimethyl-5-phenyl-2H-imidazole (1a) and 1,2-diphenylethyne (2a) under various reaction conditions (Table 1). To our delight, in the presence of [RuCl2(p-cymene)]2 (5 mol %) and Cu(OAc)2·H2O (2 equiv), the cyclization product 3aa can be generated in 40% yield (entry 1) after reacting at 100 °C in DCE for 12 h. Further introduction of Cu(OTf)2 (1 equiv) and CF3COOAg (1 equiv) as the co-oxidant can improve the yield of 3aa (entries 2−7). The solvent screening showed that the product yield is very sensitive to the variation of solvent, and TFE is a suitable solvent (entries 8−12). In addition, the addition of acid is beneficial to the reaction, and 1-AdCOOH proved to be the most effective additive (entries 13−16). In addition, substitutions of cyclohexyl and phenyl groups (1b and 1c) at the 2 position on the 2H-imidazole ring were also tolerated in the tandem reaction but exhibited slightly less reaction efficiency, probably due to the steric effect (entries 17 and 18). Furthermore, the reactions could be carried out on larger scales, and the yields of 3aa have declined but still in good yields (entries 19 and 20). However, the data implied that the scale of reactions had a crucial effect on the efficiency of this one-pot reaction.11
soquinoline has received much attention due to a wide range of biological activities (Figure 1).1 Thus, diverse
Figure 1. Pharmaceuticals and natural products bearing isoquinolines.
synthetic methods have been developed for constructing isoquinoline derivatives.2 Furthermore, chemists continued to devise novel synthetic methodologies based on the principles of atom- and step-economy.3 In 2003, Jun et al. pioneered chelation-assisted C−H activation to synthesize isoquinoline.4 Since then, different coupling partners such as imines, amines, hydrazones, and azides have also been utilized (Scheme 1, eq 1).5−7 Scheme 1. Construction of α-Substituted Isoquinolines via Tandem C−H Activation/Annulation
However, despite that synthesis of isoquinolines has achieved great success via C−H activation, highly functionalized isoquinoline derivatives have rarely been developed, and © XXXX American Chemical Society
Received: August 28, 2018
A
DOI: 10.1021/acs.orglett.8b02759 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Reaction Optimizationa
Table 2. Substrate Scope of 2H-Imidazolesa
entry
oxidant/equiv
additive
solvent
yield of 3aa (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17c 18d 19e 20f
Cu(OAc)2·H2O/2 Cu(acac)2/2 Cu(OTf)2/2 CF3COOAg/2 AgOAc/2 Cu(OTf)2/1 + CF3COOAg/1 Cu(OTf)2/1 + AgOAc/1 Cu(OTf)2/1 + CF3COOAg/1 Cu(OTf)2/1 + CF3COOAg/1 Cu(OTf)2/1 + CF3COOAg/1 Cu(OTf)2/1 + CF3COOAg/1 Cu(OTf)2/1+ CF3COOAg/1 Cu(OTf)2/1 + CF3COOAg/1 Cu(OTf)2/1 + CF3COOAg/1 Cu(OTf)2/1 + CF3COOAg/1 Cu(OTf)2/1 + CF3COOAg/1 Cu(OTf)2/1 + CF3COOAg/1 Cu(OTf)2/1 + CF3COOAg/1 Cu(OTf)2/1 + CF3COOAg/1 Cu(OTf)2/1 + CF3COOAg/1
------------PivOH 1-AdCOOH PhOCH2COOH AcOH 1-AdCOOH 1-AdCOOH 1-AdCOOH 1-AdCOOH
DCE DCE DCE DCE DCE DCE DCE TFE PhCl dioxane MeCN MeOH TFE TFE TFE TFE TFE TFE TFE TFE
40% 32% 43% 21% 33% 58% 32% 65% 33% 25% N.R. 48% 70% 77% 65% 62% 51% 32% 69% 51%
a
Reaction conditions: 1a (0.05 mmol, 1 equiv), 2a (1.2 equiv), [RuCl2(p-cymene)]2 (5 mol %), additive (2 equiv), solvent (0.5 mL) at 100 °C for 12 h under air. bIsolated yield. c1b, R4 = R5 = cyclohexyl. d1c, R4 = Me, R5 = Ph. e1a (0.3 mmol). f1a (2 mmol).
Scheme 2. Substrate Scope of Alkynesa
a
Reaction conditions: unless otherwise specified, 1 (0.05 mmol, 1 equiv), 2a (1.2 equiv), [RuCl2(p-cymene)]2 (5 mol %), Cu(OTf)2 (1 equiv), CF3COOAg (1 equiv), 1-AdCOOH (2 equiv), and TFE (0.5 mL) at 100 °C for 6−18 h, under air. bIsolated yield. c 1 (0.3 mmol). dPivOH (2 equiv).
investigating the reaction between 2,2,4-trimethyl-5-phenyl2H-imidazole (1a) and various alkynes (Scheme 2). Various diphenylethynes with valuable functional groups on the aromatic ring, either electron-donating or -withdrawing groups, could react smoothly with 1a to afford the corresponding products (3ab−3ae) in moderate to good yields (57%−85%). The substituent at the ortho-position of the phenyl ring was tolerated in the reaction system but provided the corresponding product 3af in low yield, which may be influenced by steric effects. It is noteworthy that dialkyl-substituted alkyne 1g reacted smoothly affording 3ag in 63% yield. Moreover, single isomers 3ah and 3fi were isolated by using nonsymmetrical alkynes as coupling partners. However, terminal alkynes could not react under the standard reaction conditions. We next focused our attention to the scope of the 2Himidazoles (Table 2). Pleasingly, a variety of 2H-imidazoles reacted smoothly with 2a. The substituents at the ortho-, meta-, and para-positions of the phenyl ring were all tolerated in the cascade reaction, providing corresponding products (3da−3ka) in good to moderate yields. Furthermore, the reaction of thiophene-functionalized 2H-imidazole exhibited good efficiency
a
Reaction conditions: unless otherwise specified, 1 (0.05 mmol, 1 equiv), 2 (1.2 equiv), [RuCl2(p-cymene)]2 (5 mol %), Cu(OTf)2 (1 equiv), CF3COOAg (1 equiv), 1-AdCOOH (2 equiv), and TFE (0.5 mL) at 100 °C for 6−18 h, under air. Isolated yield. b 2 (0.3 mmol). cPivOH (2 equiv).
Equipped with a set of optimized conditions (Table 1, entry 14), we explored the scope of the cross-coupling reaction by B
DOI: 10.1021/acs.orglett.8b02759 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
generate intermediate IV.12a,11 Then, the reduced Ru is reoxidized to regenerate active species Ru(II) participating in the next catalytic cycle. Finally, the C−N bond cleavage and imide hydrolysis process occurs to afford the annulation product 3aa. In summary, we have developed a new ruthenium(II)-catalyzed cascade reaction of 2H-imidazoles with alkynes, which involves direct C−H activation/cyclization/hydrolysis of imide into the carbonyl group cascade process by using 2H-imidazole as a traceless directing group. Furthermore, a broad scope of α-substituted carbonyl isoquinoline derivatives have been synthesized which could be applied to the concise synthesis of related complex molecules. Further studies of synthetic applications are under investigation in our laboratory.
for coupling with 1a, producing 3la in 69% yield. The substrates with n-butyl or phenyl groups on the 2H-imidazole ring also showed good reactivity, delivering various α-ketoneisoquinolines (3ma and 3na) in moderate yields. Depressingly, no corresponding aldehyde product 3oa was obtained when 2,2-diethyl-4-phenyl-2H-imidazole (1o) was used. In order to better illustrate of the α-substituted carbonyl isoquinolines, further transformations of the units were conducted in Scheme 3.11 Surprisingly, the versatile 3aa Scheme 3. Synthetic Applications of the Corresponding Products
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02759. Experimental procedures, structural proofs, and NMR spectra of the products (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Lin Dong: 0000-0002-8004-821X Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for the financial support from the NSFC (21572138).
Scheme 4. Plausible Reaction Mechanism
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DOI: 10.1021/acs.orglett.8b02759 Org. Lett. XXXX, XXX, XXX−XXX
Letter
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DOI: 10.1021/acs.orglett.8b02759 Org. Lett. XXXX, XXX, XXX−XXX
